The invention relates to a device and to a method for continuously producing emulsions or dispersions, particularly for producing nanoemulsions.
Emulsions and dispersions are generally produced batchwise in agitated reactors. In that case the requisite amounts of the ingredients are metered into a mixing vessel and emulsified or dispersed with high agitated input. Use is made generally for this purpose of high-performance agitators which permit the generation of cavitation forces. Alternatively a high-pressure homogenization is carried out. Monitoring of the emulsions and dispersions produced, and of the method, takes place generally only on the finished product of the corresponding mixture batch. Continuous checking of the production operation is generally not possible.
Furthermore, varying the quantities of product is possible only to a very limited extent, since in the case of a batch mixer the possible batch size is situated within a narrowly limited range. The minimum batch size must not in general be less than half of the maximum batch size.
With a view to sterile processing as well a batchwise method is problematic. In general, work takes place in open agitated tanks, so that contamination from the outside cannot be excluded. Where operation is to take place with air excluded, a costly and inconvenient method is needed for evacuating the mixing vessels in order to work under reduced pressure.
Furthermore, batch mixing devices must be of large design in order to be able to generate appropriate amounts of product. This involves considerable investment costs. Moreover, the high agitated input leads to high energy costs. Particularly for the production of nanoemulsions, especially solid lipid nanoparticles (SLN), there has to date been a lack of industrial production methods. Consequently it has not been possible to date for SLN to become established to any great extent.
SLN dispersions are customarily produced by high-pressure homogenization. Depending on the lipid and surfactant used, different particle forms are obtained. A distinction is made between hot homogenization and cold homogenization. In the case of hot homogenization, after the lipid has been melted and the active compound has been dissolved or dispersed, dispersion takes place in a hot surfactant solution. This preemulsion is then subjected to high-pressure homogenization and is then converted into a hot O/W nanoemulsion. After cooling and recrystallization, solid lipid nanoparticles (SLN) are obtained. In the case of cold homogenization, after the lipid has been melted and the active compound has been dissolved or dispersed, the drug/lipid mixture is solidified and then ground into microparticles. The particles are subsequently suspended in a cold surfactant solution and the particle suspension is subjected to high-pressure homogenization. The cavitation forces and shearing forces that occur during high-pressure homogenization are sufficient to crush the lipid microparticles into lipid nanoparticles. In the case of hot homogenization, the preemulsion is generally homogenized in the hot state in a plunger/slot homogenizer at pressures between 200 bar and a maximum of 1500 bar. This produces an emulsion whose lipid phase, on cooling, recrystallizes into SLN. For a description of the methods reference may be made to R. H. Müller, G. E. Hildebrandt, Pharmazeutische Technologie: Moderne Arzneiformen [Pharmaceutical technology: modern drug forms], wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1998, 2nd edition, pages 357 to 366.
The SLN technology serves in particular the application of active pharmaceutical, cosmetic and/or food technology compounds in a solid vehicle. The active compound vehicle may be adapted to the particular utility, and allows appropriate metering and release of the active compound. SLN represent an alternative carrier system to emulsions and liposomes. The nanoparticles may comprise active hydrophilic or hydrophobic pharmaceutical compounds and may be administered orally or parenterally. The matrix material used in this case, in contrast to the known emulsions, is a solid lipid. To ensure high bioacceptance and good in vivo breakdown, predominantly, physiologically compatible lipids or lipids comprising physiological components such as glycerides from endogenous fatty acids are used. In the course of production, as with the production of emulsions and dispersions, it is usual to use emulsifiers or surfactants as well.
One method for producing SLN dispersions is described for example in EP-B-0 167 825. The lipid nanopellets are produced by dispersing the melted lipid with water using a high-speed agitator. The desired particle size distribution is subsequently set by means of an ultrasound treatment. Agitation takes place generally at speeds in the region of 20 000 min−1.
The production of solid lipid nanoparticles with a low average particle diameter in accordance with the prior art is costly and inconvenient, since, generally, high-pressure homogenizers have to be used. Mere agitation at high speed achieves only relatively large average particle diameters of approximately 3 μm.